: This project will study genetic variation in Na/K ATPase alpha and beta subunits, and how genotype alters susceptibility to the effect of lead on blood pressure. Differences in Na/K ATPase function associated with genetic variation will be studied in vitro for the alpha 2 subunit (ATP1A2). We also propose to determine the effect of genetic variation on the relation between lead dose and blood pressure in a human population. The methods used to achieve the specific aims will include in vitro molecular biology and biochemistry studies, as well as epidemiologic studies. The Na/K ATPase alpha 2 gene is not expressed in erythrocytes. Therefore, we will study changes in DNA transcription, mRNA translation, mRNA stability, and protein phosphorylation in mammalian cells transfected with ATP1A2 genes containing specific variant sequences. Finally, we will study modification by genotype of the association between lead dose in blood or bone and blood pressure in these subjects. These studies will enhance understanding of the role of genetic susceptibility in elevated blood pressure. Specifically, the association of genetic differences in the Na/K ATPase alpha and beta subunits with increases in blood pressure will be determined, as well as the modifying effect of genotype on the relation between lead dose and blood pressure. In addition, these studies will attempt to clarify the effect of genetic variation on enzyme function to provide clues to the mechanisms of blood pressure control.